Tyler Uworld Heme

Chronic lymphocytic leukemia is associated with the over-expression of what? How does treatment of this leukemia cause cancer cell death?

Bcl-2, an anti-apoptotic protein on the mitochondrial membrane Txt with a BCL inhibitor (venetoclax) causes cancer cell death by promoting cytochrome C release from the mitochondria, which activates caspases

What is the role of cyclin-dependent kinases? What toxicity may be associated with drugs that inhibit cyclin dependent kinases?

CDKs control cell cycle progression from G1--S Toxicity--> often inhibit cellular replication in other rapidly dividing cells, particularly hematologic cells in the bone marrow

How is warfarin metabolized? What drugs are inducers of this? What drugs are inhibitors of this?

Cytochrome P450 Inducers include: carbamazepine, phenytoin, phenobarbital, rifampin, st johns wort Inhibitors: Antibiotics, azole antifungals, amiodarone, cimetidine, grapefruit juice

Why are direct oral anticoagulants (DOACs) preferred over vitamin K antagonists (VKAs) such as warfarin

DOACs have less variability in the therapeutic drug effect; unaffected by dietary changes and most medications

What is characterized by tumor lysis syndrome? How does Rasburicase help prevent and treat tumor lysis syndrome?

Hyperphosphatemia, hypocalcemia, hyperkalemia, elevated levels of LDH, and hyperuricemia Rasburicase is a recombinant version of urate oxidase, which converts uric acid into allantoin, a purine metabolite that is 5-10x more soluble than uric acid, and less likely to precipitate in the kidney

What mutation is the main cause of the chronic myeloproliferative disorders (polycythemia vera, essential thrombocytosis, and primary myelofibrosis? What causes primary myelofibrosis? What is seen in the peripheral smear?

JAK2/STAT mutation Primary myelofibrosis is caused by atypical megakaryocytic hyperplasia, which stimulates fibroblast proliferation, resulting in progressive replacement of the marrow space by extensive collagen deposition Peripheral smear characteristically shows teardrop shaped red blood cells (dacrocytes) and nucleated red blood cells

What causes the warfarin-induced skin necrosis?

A transient hyper coagulable state; Protein C has a short half-life so its anticoagulant activity is reduced quickly when warfarin therapy is initiated; during this time, the vitamin K dependent clotting factors II, IX, and X exert a procoagulant effect

What are the five classic findings of TTP? What causes acquired TTP?

1) Severe thrombocytopenia, which may cause bruising or bleeding 2) MAHA, may cause symptomatic anemia (fatigue, dyspnea on exertion, schistocytes, lowered Hb) 3) Renal damage: renal isufficiency and proteinuria 4) Neurologic damage, may cause confusion, headache, and transient focal findings 5) Fever Caused by mutation of ADAMTS-13, a vWF cleaving protease

How does hydroxyurea work in patients with sickle cell disease?

1) inhibiits ribonucleotide reductase (myelosuppression) 2) shifts globin gene transcription from beta globin to gamma globin; increasing circulating levels of fetal hemoglobin

What drug(s) are inhibitors of glycoprotein IIb/IIIa? What does this receptor normally do? This receptor is deficient or defective in what disease?

Abciximab, eptifibatide, tirofiban Usually this receptor is a fibrinogen receptor and encourages platelet aggregation Glanzmann thrombasthenia

What condition is marked by a high concentration of circulating lymphoblasts? How do you distinguish between the two lineages? What are some characteristics of the T-cell lineage?

Acute lymphoblastic leukemia (ALL) Flow cytometry: B-cell (CD19+) or T-cell (CD-3+) T-cell arises in teenagers and presents with a large mediastinal mass

What drugs are factor Xa inhibitors? What drug can be given to treat life-threatening bleeding while on these drugs?

Apixaban, rivaroxaban Andexanet alfa

What condition is bone marrow failure due to multipotent hematopoietic stem cell destruction? What medications often trigger these cases, and in what two specific ways?

Aplastic Anemia Cases are often triggered by dose-dependent bone marrow damage (chemotherapy, immunosuppressive drugs) or idiosyncratic reactions (antiseizure medicines, sulfonamides, nifedipine; can occur at any point during or after therapy)

What is characterized by episodes of hemolytic anemia following oxidative stress? What are some causes of oxidative stress? How do these patients present? What do you see on blood smear?

G6PD deficiency Stress: fava beans, dapsone, actue infection Pts have jaundice, dark urine, normocytic anemia, reticulocytosis Bite cells and heinz bodies on peripheral smear

What is the difference between CML and leukemoid reaction?

Both present similar to leukocytosis, however leukocyte (neutrophil) alkaline phosphatase level is normal or elevated in a leukemoid reaction but decreased in CML

What sort of therapy should be implemented in patients receiving chronic red blood cell transfusions? How does this treatment help the future of the patient?

Chelation therapy with deferoxamine Deferoxamine prevents iron-induced cardiotoxicity and congestive heart failure from developing

What condition is commonly associated with normocytic anemia? What causes this anemia? What signaling molecule promotes survival of erythrocyte precursors?

Chronic kidney disease Released production of erythropoietin by the kidneys JAK2/STAT

In high volume blood transfusion, what may lead to hypocalcemia? How will this present in a patient?

Citrate anticoagulants can chelate plasma calcium, leading to hypocalcemia; this causes peripheral neuromuscular excitability (paresthesia, muscle spasms)

What is the definition of pancytopenia? What can cause pancytopenia? What drug used for sickle cell anemia may cause pancytopenia?

Decrease in all 3 blood cell lineages Caused by hematopoietic stem cell dysfunction, bone marrow infiltration, or peripheral destruction of mature blood cells Hydroxyurea

What is the underlying biochemical feature of megaloblastosis? How might this present in chronic alcoholics?

Defect in DNA synthesis In chronic alcoholics, megaloblastic macrocytic anemia can result from a nutritional deficiency of B12 or Folate, which impairs synthesis of purine and pyrimidine bases

What is the MOA of apixaban? What does this lead to?

Direct factor Xa inhibitor Reduced conversion of prothrombin to thrombin

What drugs are used for treatment of heparin-induced thrombocytopenia (HIT)? What form of heparin often causes heparin-induced thrombocytopenia?

Direct thrombin inhibitors: Bilvalirudin, Argatroban, Dabigatran Unfractionated heparin use

HFE protein mutations are the most common cause of what disorder? How does inactivation of the HFE protein lead to iron overload? What are some risks associated with this disorder?

Hemochromatosis Inactivated HFE protein results in decreased hepcidin synthesis by hepatocytes (low hepcidin increases ferroportin expression) and increased DMT1 expression by enterocytes (this increases iron absorption) Increased risk for liver cirrhosis and HCC; may also cause cardiomyopathy

Bleeding after a tooth extraction and history of hemarthrosis are suggestive of what condition? This leads to decreased levels of which factors? What does this lead to? What will induce clotting in this patient?

Hemophilia Decreased levels of factor VIII or IX leads to failure to convert prothrombin into thrombin, and deficient thrombus formation The addition of thrombin to the blood of a patient with hemophilia results in clotting

What bug causes infectious mononucleosis? What malignant conditions is this infection associated with? What specific types of antibodies are produced with this condition?

EBV Burkitt Lymphoma and nasopharyngeal carcinoma EBV infection induces heterophile antibodies, react to antigens from animal erythrocytes (monospot test)

What is virchow's triad? What may this cause?

Endothelial injury, venous stasis, and a hypercoagulable state (caused by malignancy, active smoking, age, etc) This may cause a venous thromboembolism to develop

What drugs are the LMWH? What is their MOA?

Enoxaparin, Dalteparin Binds and activates antithrombin III; which binds to factor Xa and stops factor Xa from converting prothrombin to thrombin

What is produced by peritubular fibroblast cells in the renal cortex in response to decreased renal oxygen delivery? How does this hormone function?

Erythropoietin (EPO) Acts on erythrocyte precursors in the bone marrow to increase red blood cell production

What disorder presents with intramuscular hemorrhage, hemarthrosis, and delayed bleeding after procedures? What is the inheritance pattern? What laboratory results are associated with this condition?

Hemophilia X-linked recessive coagulopathy Lab tests show aPTT prolongation, other tests usually normal

Which chemotherapeutic agents inhibit topoisomerase II? How exactly do these agents work? Which cancers are these agents most effective against?

Etoposide, Teniposide--> chromosomal breaks accumulate in dividing cells, ultimately causing cell death. Cell cycle arrest in G2 and S phases Testicular cancer, small cell lung cancer

THe presence of erythroid precursors in organs such as the liver and spleen is indicative of what condition? What causes this condition'?

Extramedullary hematopoiesis, a condition characterized by erythropoietin-stimulated, hyperplastic marrow cell invasion of extramedullary organs Frequently caused by severe chronic hemolytic anemias (B-thalassemia)

What is the most common indolent non-hodgkin lymphoma in adults? How does it present? WHat is the cytogenetic change in this condition?

Follicular lymphoma Presents with painless waxing and waning (fluctuating) lymphadenopathy t(14;18)--> over expression of BCL2

What cancer is characterized by aggregates of packed follicles that obscure the normal lymph node architecture? What is the translocation associated with this?

Follicular lymphoma t(14;18) translocation; causes over-expression of antiapoptotic BCL-2

What mutation is associated with a factor V leiden mutation? What are the major clinical manifestations of this condition?

Guanine--> adenine Complications include DVT, cerebral vein thrombosis, recurrent pregnancy loss Resistance to degradation by activated protein C

What B cell neoplasm is predominantly found in middle-aged men and characterized by bvone marrow failure and infiltration into the reticuloendothelial system, causing massive splenomegaly? What are some other typical features?

Hairy cell leukemia Dry tap (unsuccessful bone marrow aspiration) and presence of lymphocytes with cytoplasmic projections

How is erythrocytosis defined? How does one distinguish between relative and absolute erythrocytosis?

Hematocrit level >52% in men, >48% in women Measure RBC mass; normal is relative, increased is absolute

What are the ideal anticoagulants for most patients with thromboembolic disease in pregnancy?

Heparins, specifically low molecular weight heparin (enoxaparin)

What polypeptide acts as a central regulator of iron homeostasis? What increases the synthesis of this polypeptide? Inhibits? What cell type secretes this polypeptide?

Hepcidin High iron levels and inflammatory conditions increase it Hypoxia and increased erythropoiesis lowers it hepatocytes

What is hypochromic, microcytic anemia most commonly due to? What must be ruled out in a patient with this condition?

Iron deficiency anemia Blood loss, especially occult loss from the GI tract must be ruled out

What is a serious complication of chronic hemolytic anemia and frequent blood transfusions? What is the cardinal histologic finding?

Iron overload (hemosiderosis) Hemosiderin accumulation--> Kupffer cells containing coarse, yellow-brown cytoplasmic granules

what is the MOA of Lenalidomide? What condition does Lenalidomide treat? What other drugs are used for the same condition?

Lenalidomide increases E3 ubiquitin ligase binding to transcription factors over-expressed in myeloma, resulting in increased transcription factor destruction by the proteasome and cancer cell death Txt for multiple myeloma Another drug to treat multiple myeloma is bortezomib, which blocks proteasome activity

What condition is significant leukocytosis that results in response to an underlying condition, commonly severe infection. What does blood smear show? What are the LAP levels in this condition?

Leukemoid reaction Blood smear shows neutrophilia with reactive features (Dohle bodies: blue cytoplasmic inclusions of rough ER) as well as increased neutrophil precursors (bands, metamyelocytes, myelocytes)

What are the five major receptors invovled in stimulating the vomiting reflex in the area postrema and adjacent vomiting center? What receptors are particularly useful in txt of chemotherapy-induced vomiting?

M1 muscarinic D2 dopaminergic H1 histaminergic 5HT3 serotonergic Neurokinin 1 (NK1) 5HT3 and NK1

What drug commonly is used to treat ectopic pregnancy? What kind of drug is this? What enzyme does it inhibit? What intermediate accumulates intracellularly?

Methotrexate Folic acid antagonist Competitively inhibits dihydrofolate reductase DHF polyglutamate will accumulate in cells

What plasma cell malignancy is associated with significant production of secretory proteins (monoclonal immunoglobulins)? What is the treatment for this condition? what is the MOA of the pharmacological agent?

Multiple myeloma Txt with proteasome inhibitors (bortezomib) These drugs block the degradation of ubiquitinated proteins by the proteasome, leading to accumulation of abnormally folded proteins that trigger cellular apoptosis

What condition is a clonal hematologic neoplasm marked by >1 cytopenias and cellular dysplasia (oval macrocytic erythrocytes, hyposegmented granulocytes? What is seen on bone marrow evaluation?

Myelodysplastic syndrome Bone marrow shows hypercellular marrow, mild or moderate increase in myeloblasts (<20% of total cells), and dysplastic erythrocytes/granulocytes

What effect does CO poisoning have on oxygens binding affinity to hemoglobin? How does it affect oxygen unloading from hemoglobin in tissues? How does it affect carboxyhemoglobin concentrations, partial pressure of oxygen, and methemoglobinemia?

Prevents oxygen binding to hemoglobin Reduces oxygen unloading from hemoglobin into tissues increases carboxyhemoglobin, does not affect partial pressure of oxygen and does not precipitate methemoglobinemia

What is the dose limiting side effect of vincristine therapy? What causes this toxicity?

Neurotoxicity, in the form of peripheral neuropathy This toxicity results from failure of microtubule polymerization in neuronal axons

What patient population has much higher rates of lymphoma than the general population? What underlying infection acts to promote uncontrolled B lymphocyte proliferation

Patients with HIV Underlying EBV infection acts synergistically with HIV to promote uncontrolled B lymphocyte proliferation

Why might an individual with sickle cell develop megaloblastic anemia?

Patients with sickle cell disease have increased folic acid requirements due to increased erythrocyte turnover; they are prone to developing relative folic acid deficiency and megaloblastic anemia

What are common triggers for drug induced hemolytic anemia? Why?

Penicillins and cephalosporins, anti-inflammatory medications--> typically cause hemolysis by binding to the erythrocyte surface, which creates a hapten for IgG attachment; antibody coated erythrocytes are then phagocytized by splenic macrophages, leading to extravascular hemolysis

What types of cancer are polyclonal? Monoclonal?

Polyclonal-- Benign Monoclonal-- Malignant

What effect on thrombin time, factor Xa, and PTT?

Prolonged thrombin time, prolonged PTT, decreased activity of factor Xa

What can be given to reverse the effects of heparin?

Protamine sulfate, causes chemical inactivation

What two lab values are altered during warfarin treatment? Why?

Prothrombin time (PT)--> decreased levels of factor VII International Normalized Ratio (INR), a ratio of the patient's PT to a control

What causes abnormal bleeding in patients with uremia? What effect does this have on bleeding time, platelet count, prothrombin time, and activated partial thromboplastin time?

Qualitative platelet disorder Prolonged BT, normal platelet count, PT, and aPTT

Hereditary spherocytosis results from what type of abnormality? What are some classic manifestations? What is seen on peripheral blood smear?

RBC cytoskeleton abnormalities, most commonly spectrin and ankyrin Hemolytic anemia, jaundice, splenomegaly are classic manifestations Spherocytes seen on blood smear

What is the most common cause of elevated platelet count in all age groups? What role do inflammatory cytokines have in this presentation?

Reactive thrombocytosis High levels of inflammatory cytokines (IL-6) prompt the liver to release thrombopoietin Can be seen in chronic infection, rheumatologic dx, burns

What cells sense hypoxia and respond by synthesizing and releasing erythropoietin?

Renal cortical cells

What condition is characterized by repeated splenic infarctions that ultimately result in splenic atrophy and fibrosis? When is this process typically complete by? What affect does autosplenectomy have on patients?

Sickle cell disease Late childhood/adolescence Patients are predisposed to infections with encapsulated bacterial organisms

What are the common causes of DIC? What is DIC characterized by? What do the lab results show?

Snake bites, sepsis, trauma, obstetric complications, acute pancreatitis, etc Characterized by widespread activation of the coagulation cscade with formation of microthrombi Lab: prolonged PT/PTT, thrombocytopenia, low fibrinogen (a consumptive coagulopathy)

Glomerulonephritis, a photosensitive skin rash, and arthralgia in a young woman are suggestive of what? What antibodies in these patients can cause paradoxical aPTT prolongation and a false-positive RPR/VDRL? What are these patients at risk for?

Systemic lupus erythematosus (SLE) Antiphospholipid antibodies Risk for venous and arterial thromboembolism and unexplained, recurrent pregnancy loss

Why is the therapeutic effect of warfarin delayed for 3-5 days?

Warfarin only inhibits gamma carboxylation of NEW vitamin K-dependent clotting factors, therapeautic efficacy is delayed until preexisting clotting factors in the plasma are consumed. Ex: Factor II has a long half life (3 days)

what role does the MDR1 gene have in avoidance of anticancer agents?

The human muldidrug resistance gene produces P-glycoprotein, an ATP-dependent efflux pump; it actively removes chemotherapeutic agents, particularly hydrophobic agents like anthracyclines

How do cancer cells avoid immune recognition? How are monoclonal antibodies effective against cancer cells?

They overexpress programmed death-ligand 1 (PD-L1), which binds the PD-1 receptor on cytotoxic T cells, inhibiting their response Monoclonal antibodies that block PD-L1 and PD-1 are effective against cancers that express high levels of neoantigens on their surface bc these tumors are particularly susceptible to immune recognition by cytotoxic T cells

What is released in abruptio placentae that causes DIC? What is the function of this released substance? How does DIC typically present?

Tissue factor, a procoagulant that activates the coagulation cascade DIC classically presents with thrombocytopenia, and bleeding from mucosal surfaces (gums) and IV line sites

What drug is used in HER2+ breast cancer? What type of receptor is HER2?

Trastuzumab; tyrosine kinase receptor

Which form of heparin anticoagulant is most effective in inactivating thrombin? Why?

Unfractionated heparin Unfractionated heparin has a pentasaccharide chain long enough (>18 units) to bind both antithrombin and thrombin Unfractionated heparin has equal activity against factor Xa and thrombin, while LMWH has greater activity against factor Xa than thrombin

What drug class acts by inhibiting microtubule funciton? What phase of the cell cycle is most affected? What are some common side effects of these drugs?

Vinca alkaloids (vincristine, vinblastine) M phase Vincristine-- neurotoxicity, peripheral neuropathy

Deficiency of which enzyme is associated with coiled hair, perifollicular keratosis, hemorrhage, easy bruising, bleeding gums, and loose teeth? What effect does this have on PT, PTT and platelet count?

Vitamin C deficiency/Scurvy PT, PTT, and platelet count will be normal

What enhances clotting through augmentation of platelet binding and stabilization of factor VIII? What are symptoms for deficiency? What drug is used to treat this? What is the MOA?

Von villebrand factor Present with increased bruisability and prolonged mucosal bleeding Desmopressin can alleviate bleeding through endothelial release of vWF

How does pyruvate kinase deficiency cause hemolytic anemia? What affect might this have on the spleen?

due to failure of glycolysis and resultant failure to generate sufficient ATP to maintain erythrocyte structure Reticuloendothelial cells in the splenic red pulp are involved in removal of damaged RBCs, their increased activity in the setting of pyruvate kinase deficiency causes them to undergo hyperplasia

What causes major chronic pathologic changes in the spleens of patients with sickle cell anemia?

repetitive splenic infarctions caused by splenic microvessel occlusion. Fibrosis, brownish discoloration, and eventual autosplenectomy ultimately result

What is in the blue cytoplasm of reticulocytes?

residual Ribosomal RNA

What is the translocation associated with Burkitt Lymphoma? What is overexpressed? What is seen on histology?

t(8;14) C-myc is overexpressed; transcriptional activator Histo: tingible body macrophages; starry sky appearance